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Functional consequences of P/Q-type Ca2+ channel Cav2.1 missense mutations associated with episodic ataxia type 2 and

Edwin Wappl1, Alexandra Koschak, Michael Poteser

  • 1Institut für Biochemische Pharmakologie, Abteilung Pharmakologie und Toxikologie, Institut für Pharmazie, Universität Innsbruck, Peter-Mayrstrasse 1, A-6020 Innsbruck, Austria.

The Journal of Biological Chemistry
|December 14, 2001
PubMed

Insights

Investigating P/Q-type Ca(2+) channel mutations reveals functional consequences for ataxia. Some mutations cause channel dysfunction, supporting loss-of-function as a cause of episodic ataxia type 2 and progressive ataxia.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Ataxia, including episodic ataxia type 2 (EA-2) and progressive ataxia (PA), is linked to mutations in the alpha1A (Ca(v)2.1alpha(1)) subunit of P/Q-type Ca(2+) channels.
  • Understanding the functional impact of these mutations is crucial for elucidating ataxia pathophysiology.

Purpose of the Study:

  • To investigate the functional consequences of specific P/Q-type Ca(2+) channel alpha1A subunit mutations (R1279Stop, AY1593/1594D associated with EA-2, and G293R associated with PA).
  • To determine if these mutations lead to a loss of channel function underlying ataxia.

Main Methods:

  • Human alpha1A cDNA with specific mutations were expressed in Xenopus oocytes and tsA-201 cells.
  • Electrophysiological analyses (current density, single channel conductance, current-voltage relationships, inactivation, recovery from inactivation) and biochemical analysis were performed.

Main Results:

  • The G293R mutation reduced current density without altering single channel conductance.
  • R1279Stop and AY1593/1594D mutations resulted in non-functional channels in tsA-201 cells, but AY1593/1594D showed partial function in oocytes.
  • G293R and AY1593/1594D shifted the current-voltage relationship, enhanced inactivation, and AY1593/1594D slowed recovery from inactivation. G293R altered fast channel gating.

Conclusions:

  • The findings support the hypothesis that a significant loss of P/Q-type Ca(2+) channel function contributes to the pathophysiology of EA-2 and PA.
  • Unlike some other EA-2 mutations, AY1593/1594D and G293R mutations result in at least partially functional channels.

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